Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas

Thalidomide is active in patients with refractory myeloma. Seventeen patients (nine men/eight women, median age 73 years) with multiple myeloma (MM) were treated with thalidomide. Fifteen patients had refractory disease and two untested relapse. The median dose of thalidomide was 500 mg (range, 200-800 mg). Nine of the 17 patients (53%) responded. The response rate was significantly higher in patients with no extramedullary disease than in those with soft tissue masses (75% CI: 43-95% versus 0%; P = 0.01)). Of note, no decrease in the size of soft tissue plasmacytomas was observed in all the five patients who had extramedullary involvement. This data suggests that the mechanism of action and effectiveness of thalidomide might depend on the site of the tumour cells.     

Bortezomib combination therapy in multiple myeloma

Bortezomib was approved for the treatment of multiple myeloma (MM) in 2003. Since then several bortezomib-based combination therapies have emerged. Although some combinations have been preceded by preclinical investigations, most have followed the inevitable process in which active (or potentially active) drugs are combined with each other to create new treatment regimens. Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide, and/or lenalidomide have resulted in high response rates. Despite the higher and often deeper response rates and prolongation of progression-free survival with bortezomib-based multiagent regimens, an overall survival (OS) advantage has not been demonstrated with most combinations compared to the sequential approach of using anti-myeloma agents, particularly in patients less than 65 years of age with newly diagnosed myeloma. The unique properties of some of these regimens can be taken into account when choosing a particular regimen based on the clinical scenario. For example, the combination of bortezomib, thalidomide, and dexamethasone (VTD) has particular value in renal failure since none of the drugs need dose modification. Similarly, the combination chemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) is of particular value in patients presenting with aggressive disease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials are testing combinations of bortezomib with several other classes of agents, including monoclonal antibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3-kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase.     

多发性骨髓瘤伴髓外浸润25例临床分析

目的 研究多发性骨髓瘤(MM)伴髓外浸润患者的临床特点及治疗.方法 分析我科2006年7月至2008年7月收治的25例MM伴髓外浸润的患者,男:女为15:10,中位年龄55.2(30～65)岁.其中IgA 10例,IgG 9例,轻链λ5例,IgD 1例.髓外浸润最常见部位是肌肉和椎管.结果 在诊断时即有髓外浸润的患者,应用传统的化疗方案,如美法仑、泼尼松、沙立度胺或长春新碱、阿霉素、地塞米松,总有效率达到8/10例,随着髓内病变的好转髓外浸润也明显好转.而在后期出现的髓外浸润应用传统的化疗方案往往无效,我们选用含有硼替佐米的方案或顺铂、环磷酰胺、足叶乙甙、泼尼松(DECP),取得了较好的效果.接受DECP化疗的有效率为66.7%(10/15),接受硼替佐米的有效率为4/8例.结论 MM疾病进展后伴髓外浸润患者治疗效果差,进展迅速,常规化疗方案治疗效果较差,应尽早应用新药以及一些二线化疗方案.     

Bortezomib in relapsed multiple myeloma complicated by extramedullary plasmacytomas

A 58-year-old man suffered relapse of multiple myeloma complicated by large intra-abdominal extramedullary plasmacytomas and severe hepatic impairment secondary to biliary obstruction. Previous treatment had included two types of combination chemotherapy and high-dose therapy with autologous stem cell transplant. Combination therapy with bortezomib and dexamethasone resulted in partial response of the plasmacytomas and complete resolution of his hepatic impairment. Extramedullary plasmacytomas are rare. This report lends support to the efficacy of bortezomib in the treatment of plasmacytoma and describes the safe use of bortezomib despite hepatic upset.     

Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation.

Treatment options for patients with myeloma who relapse after allogeneic stem cell transplantation are limited. Thalidomide, an antineoplastic agent, has been shown to be effective in multiple myeloma through proposed mechanisms that may include angiogenesis inhibition. Herein we report successful thalidomide treatment of four patients who relapsed following allogeneic transplantation, three of whom had predominantly extramedullary relapse. Thalidomide was well tolerated in all patients; in two patients interferon-alpha was subsequently added to thalidomide as maintenance therapy without worsening graft-versus-host disease. We suggest that extramedullary myeloma is particularly sensitive to thalidomide, speculating that growth biology may in part be dependent on angiogenesis.     

Extensive soft-tissue involvement by plasmablastic myeloma arising from displaced humeral fractures

A 44-yr-old man with IgG-lambda multiple myeloma reached a complete response after induction chemotherapy and autologous stem cell transplantation and maintenance therapy with interferon α2b and prednisone 4 yr later, he presented an increase in the M-protein plus extramedullary myeloma involvement with sacrum and clivus plasmacytomas. Treatment with bortezomib, cyclophosphamide and dexamethasone plus local radiotherapy was initiated. The patient developed a bilateral humeral pathological fracture. Surgical osteosynthesis of both humeri was performed with no immediate complications. Two months later, he developed a prominent swelling in both deltoid areas with fever and high serum LDH levels. X-ray examination showed a displacement of bone fragments of both humeri. Humerus CT scan showed a bilateral fracture in proximal diaphysis with posterior displacement. A magnetic resonance of right scapular region revealed a very extensive infiltration originated in the humerus. A fine-needle punction showed a diffuse plasmablastic infiltration. This case illustrates an atypical presentation of extramedullary myeloma with extensive soft-tissue involvement, originated at the fractured lytic lesions, which was likely triggered by bone surgery. This direct mechanism of myeloma spread has been observed in experimental myeloma mouse models.     

Extramedullary plasmacytoma: report of two cases with uncommon presentation

Lymph node infiltration by monoclonal plasma cells can occur either in aggressive forms of myeloma or may represent regional extension of extramedullary plasmacytomas, whereas lymph node plasmacytoma presenting as a solitary extramedullary plasmacytoma is very unusual. We report two cases of lymph node plasmacytomas without systemic disease diagnosed after surgical excision. Clinical remission was achieved after local radiotherapy although one patient relapsed with multifocal extramedullary plasmacytomas 20 months after radiotherapy.     

Thalidomide, lenalidomide and bortezomib in the management of newly diagnosed multiple myeloma

The field of multiple myeloma therapeutics has been an active one for many years, but perhaps no more so than in the past decade. The introduction of thalidomide, lenalidomide and bortezomib in the treatment of this disease highlights clinical advances made during this period. While these agents were initially utilized in the setting of relapsed and refactory disease, they are now part of the therapeutic armamentarium for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. The principles of management applied in the care of newly diagnosed multiple myeloma are reviewed in this article, along with the clinical studies supporting the use of thalidomide, lenalidomide and bortezomib in newly diagnosed multiple myeloma. Management of treatment-related side effects is also discussed, since it constitutes a critical element in the successful management of patients with this disease. Combination regimens utilizing thalidomide, lenalidomide and bortezomib are also highlighted, as these regimens are likely to play an increasingly important role in myeloma therapy in the future.     

Progressive Myeloma after Thalidomide Therapy in a Patient with Immature Phenotype of Myeloma (Plasma) Cells

In our experience with thalidomide treatment for refractory multiple myeloma (MM), most patients with progressive disease (PD) did not show an increase in M-protein despite the tumor burden of myeloma cells. This finding led us to suspect that proliferation of immature myeloma cells showing MPC-1(-)/CD49e(-) phenotype may be a sign of PD. We report the results of consecutive analysis of the phenotype of myeloma (plasma) cells in an MM patient with PD during treatment with thalidomide. The myeloma cells decreased by thalidomide therapy were mature (MPC-1(+)/CD49e(+)) and intermediate (MPC-1(+)/CD49e(-)) types. When the patient was in the PD state, extramedullary plasmacytoma was recognized without proliferation of myeloma cells in the bone marrow (BM). The phenotype of myeloma (plasma) cells in both of these locations was that of immature myeloma cells (MPC-1(-)/CD49e(-)), and they showed decreased intensity of CD38 expression. The level of immunoglobulin G (IgG) in serum was decreased, and myeloma (plasma) cells in BM did not increase in PD. Although these clinical features may not be specific to MM patients in PD undergoing treatment with thalidomide, we suggest that immature myeloma cells may be resistant to thalidomide.     

Plasmacytoma relapses in the absence of systemic progression post-high-dose therapy for multiple myeloma

Autologous (ASCT) and allogeneic stem cell transplantations (alloBMT) are well-established therapies for multiple myeloma. However, patients continue to relapse at a constant rate. We present here 15 out of 163 patients who underwent SCT and relapsed with plasmacytomas only without evidence of bone marrow disease progression (14/147 post-ASCT and 1/16 post-alloBMT). The median time from SCT to plasmacytoma relapse was 24 months. The sites of plasmacytoma included bone, skin, rectum, and testicles. Five patients were treated with local radiotherapy, while seven patients received a combination of radiotherapy and chemotherapy or thalidomide, and two patients received chemotherapy alone with or without thalidomide. The recipient of alloBMT was initially treated with VAD-chemotherapy and local radiotherapy followed by a mini-allograft from the original donor. Eleven patients died at a median of 10 months following diagnosis of the plasmacytoma. Four are still alive, 12-20 months post-plasmacytoma diagnosis. These cases of unconventional disease recurrence are likely to be seen due to sub-clinical seeding of tumour cells suggestive of the presence of an extramedullary (EM) clone of plasma cells with a high degree of chemoresistance. We also review all the available data in the literature for the optimal therapy for patients with isolated EM relapse.     

Management of myeloma-associated renal dysfunction in the era of novel therapies

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.     

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.     

Plasma cell leukaemia and other aggressive plasma cell malignancies

Extramedullary plasma cell cancers, such as plasma cell leukaemia (PCL) and multiple extramedullary plasmacytomas (MEP) are very aggressive malignancies. These can be primary (de‐novo) or secondary due to progressive prior multiple myeloma (MM). Recent reports suggest an increase in incidence of these disorders. Compared to MM, organ invasion is common in PCL, while soft tissue tumors involving the head, neck or paraspinal area are common sites for MEP. Markers of poor prognosis are frequently observed in these extramedullary forms of plasma cell cancers, and survival is significantly inferior compared to patients with MM. Conventional chemotherapeutic and radiotherapy approaches have been employed with variable results. Even high dose chemotherapy with autologous stem cell rescue has not been able to demonstrate consistent improvement in survival outcome. Although not specifically evaluated, novel anti‐plasma cell agents, such as the proteasome inhibitor bortezomib, and immunomodulatory drugs, such as lenalidomide, appear to be active against these aggressive cancers. Clinical and translational research directed at improved understanding of disease biology and development of novel therapeutics is urgently needed.     

Subcutaneous plasmacytomas with tropism to sites of previous trauma in a multiple myeloma patient treated with an autologous bone marrow transplant

We report the case of a 59-year-old woman with Durie-Salmon stage IIIB IgGkappa multiple myeloma (MM), who presented 83 days after autologous hematopoietic stem cell transplant (HSCT) with multiple subcutaneous plasmacytomas. These lesions were confined exclusively to sites where the patient had sustained local trauma. The patient had no pre-transplant history of extramedullary disease and no evidence of plasma cells in the peripheral blood at any time throughout the course of her disease. This case represents the first report of refractory MM presenting as multiple subcutaneous plasmacytomas with specific tropism to sites of previous trauma. Selection of tumor cell subclones with unique chemokine receptor expression profiles that may explain this clinical observation is discussed.     

Nonmyeloablative allogeneic peripheral blood stem cell transplantation for multifocal extramedullary plasmacytomas progressing after autologous transplantation

Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area.     

Multiple myeloma: 2018 update on diagnosis,risk‐stratification,and management

Multiple myeloma accounts for approximately 10% of hematologic malignancies. The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events: CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. Patients with del(17p), t(14;16), and t(14;20) have high‐risk multiple myeloma. Patients with t(4;14) translocation and gain(1q) have intermediate‐risk. All others are considered standard‐risk. Initial treatment consists of bortezomib, lenalidomide, dexamethasone (VRd). In high‐risk patients, carfilzomib, lenalidomide, dexamethasone (KRd) is an alternative to VRd. In eligible patients, initial therapy is given for approximately 3‐4 cycles followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT at first relapse. Patients not candidates for transplant are treated with VRd for approximately 8‐12 cycles followed by lenalidomide or lenalidomide plus dexamethasone. After ASCT, lenalidomide maintenance is recommended for standard risk patients, while maintenance with a bortezomib‐based regimen is needed for patients with intermediate or high‐risk disease. Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse. Aggressive relapse with extramedullary plasmacytomas or plasma cell leukemia may require anthracycline containing combination chemotherapy regimens.     

Novel Therapies in Multiple Myeloma

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.     

P53 deletion may drive the clinical evolution and treatment response in multiple myeloma

We report a patient with multiple myeloma presenting with a paraspinal plasmacytoma with a marked dissociation between the response obtained in bone marrow (BM) infiltration and that achieved in soft tissue masses. While a complete remission was reached and maintained in BM, extramedullary plasmacytomas were refractory to every line of treatment. Genetic analysis identified the presence of t(4;14) and RB deletion in myeloma cells of both origins. However, a P53 deletion was only detected in plasma cells from extramedullary plasmacytomas. This finding suggests that P53 deletion has a role in the lack of treatment response of extramedullary plasmacytomas.     

Primary pulmonary plasmacytoma: a case report

Most extramedullary plasmacytomas are associated with the upper respiratory tract. Primary pulmonary plasmacytomas are rare, and the treatment is surgical excision. This malignancy advances to multiple myeloma in a minority of patients. The patient in our case report is the first to experience renal failure due to hematologic monoclonal gammopathy. Postoperatively, serum protein electrophoresis reverted to normal.     

Treatment with a proteasome inhibitor, bortezomib, for thalidomide-resistant multiple myeloma

A proteasome inhibitor with a new molecular target (PS-341: bortezomib) was recently developed, and its efficacy in the treatment of refractory multiple myeloma has been reported in the United States. Here, we present a 54-year-old Japanese male patient with refractory multiple myeloma resistant to thalidomide. In 1998, the patient was diagnosed as having multiple myeloma (IgG-kappa) and underwent chemotherapy, autologous hematopoietic cell transplantation and interferon therapy, but the disease recurred. In December 2002, thalidomide and high-dose dexamethasone therapy was initiated, and while this combination therapy was effective at first, the multiple myeloma became unresponsive. On 23 June 2003, bortezomib therapy with the following regime was therefore started: 2.2 mg (1.3 mg/m2) of bortezomib was injected intravenously on days 1, 4, 8 and 11, and after a one-week break, another cycle was performed. Starting on day 8 of the administration, the serum total protein, IgG, serum calcium and LDH levels decreased rapidly, and after day 45 of the administration, blood transfusion was no longer needed. Since this is the first report of the use of bortezomib in the treatment of refractory multiple myeloma in Japan, further monitoring of this patient will provide extremely valuable information for developing a therapy against this disease.